P780: COMBINATION THERAPY OF ELTROMBOPAG AND CYCLOSPORINE A CAN IMPROVE HEMATOPOIESIS IN PATIENTS WITH LOWER RISK MYELODYSPLASTIC SYNDROME
Authors: L. Song, C. Chang
Journal: HemaSphere (2022)

Background: Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal myeloid disorders characterized by ineffective hematopoiesis and cytopenias, with variable risks of progression to acute myelogenous leukemia (AML). Peripheral blood cytopenias (thrombocytopenia, leucopenia, and anemia) are the major sources of morbidity and mortality for lower-risk MDS (LR-MDS) patients. Among the cytopenias, thrombocytopenia is a severe complication of ineffective hematopoiesis and is associated with poor overall survival.Eltrombopag (EPAG) is an orally administered small-molecule, nonpeptide thrombopoietin (TPO) receptor agonist, C-mpl is a TPO receptor expressed on megakaryocytes, HSCs, and progenitor cells. The interaction between EPAG and megakaryocytes regulates platelet production, maturation, and release through the binding of C-mpl on megakaryocytes. Aims: The above studies provided a rationale for the use of the combination of EPAG and CysA in the treatment of LR-MDS. In this study, we investigated the efficacy and safety of the combination of EPAG and CysA in LR-MDS in a non-randomized phase II investigator-initiated trial (IIT). Methods: Herein, a non-randomized phase II investigator-initiated trial was conducted to investigate the efficacy and safety of the combination of EPAG and cyclosporine A (CysA) in LR-MDS. EPAG dose was escalated from 50 mg/day to a maximum of 100 mg/day. The dose of CysA is 3–5 mg/kg/d to maintain serum trough concentration at 200 mg/mL. Results: All the 31 patients were evaluated for response at the primary endpoint. Among them, 21 (67.7%) patients achieved treatment response in at least one eligible lineage with an objective response rate (ORR), 4 (12.9%) patients achieved a CR, 5 (16.1%) patients achieved bi-lineage responses (HI-PE R), 11 (24.3%) patients achieved platelet lineage responses (HI-P R), and 1 (3.2%) patient achieved erythroid lineage response (HI-E R). The median time to response was 8 (range, 2–24) weeks. Of the 21 patients eligible for an erythroid lineage response (RBC transfusion-dependent or Hb <90 g/L),10 patients (47.6%) had responded by the endpoint and the platelet response rate was 64.5% (20/31). The median increase in Hb levels and platelets was from 60.4±18.2 g/L to 68.0±21.2 g/L (P=0.015) and from 12.3±11.2×109/L to 32.5±37.3×109/L (P=0.003). The median DORs of HI-E and HI-P were not achieved, but the response rates of erythroid and platelet lineages in 20 months were 80.0% and 70.6%, respectively. The RBC and platelet transfusion-dependent rate decreased from 42.9% (9/21) to 28.6% (6/21) (X2=0.933，P=0.334) and from 58.0% (18/31) to 25.8% (8/31) (X2=6.624, P=0.010). respectively. The median time to response is 8 weeks. All 31 patients were evaluated for toxicity, and the treatment was found to be well-tolerated. The most commonly reported adverse events (AEs) of any grade were nausea (6/31,19.4%), elevated liver transaminases (4/31,12.9%), and headache (3/31,9.7%); no severe AEs had been reported until the cutoff date. Summary/Conclusion: In conclusion, our results indicated that the addition of Epag to CysA is well-tolerated and is an effective treatment for patients with low to intermediate-1 risk MDS. These response rates are better than CysA monotherapy, especially HI-P. Also, the hematological responses are durable, although continued Epag administration might be necessary. Further large prospective and controlled studies are warranted to define the role of this combination treatment in LR-MDS in comparison to CysA